tbuckley/cabot-search huggingface dataset:
The role of Chemotherapy Response Score (CRS) in the decision making process for patients with advanced high grade serous ovarian cancer undergoing neoadjuvant chemotherapy.
Authors: Claudia Marchetti, Raffaella Ergasti, Filippo Maria Capomacchia, Diana Giannarelli, Carolina Maria Sassu, Gian Franco Zannoni, Giovanni Scambia, Anna Fagotti
Journal: Journal of Clinical Oncology (2023)

5591 Background: The role of chemotherapy response score (CRS) in predicting PARP inhibitors (PARPi) response for high grade serous Advanced Ovarian Cancer (AOC) patients undergoing Neoadjuvant Chemotherapy (NACT) has never been investigated. Also, the correlation between CRS and Homologous Recombination status (HRs) is unclear. Methods: In this observational retrospective study, we collected data from patients with high grade serous AOC, FIGO stage III-IV, undergoing NACT and subsequent Interval Debulking Surgery (IDS) from 2017 to 2021. KELIM score, CRS and BRCA status were considered; additionally, HRs (Foundation test) was reported when available. Primary endpoint was Progression Free Survival (PFS) according to CRS (CRS 1/2 vs 3) in patients receiving PARPi. Results: We enrolled 309 patients; 102 had CRS3 and 193 had CRS1/2 (14 were undetermined). Patients with CRS3 and PARPi maintenance showed the best prognosis, compared to all other subgroups (median PFS Not Reached, p=0.014); additionally, in the BRCA wild type population, CRS3 was predictive of longer survival (median PFS for the CRS3+PARPi BRCAwt population 24 months compared with 15 months for the CRS1/2+PARPi BRCAwt patients, p=0.041). Furthermore, among the 44 patients with known HRs, 59.1% of HR Deficiency (HRD) positive patients had CRS3, conversely 22.7% of HRD negative ones had a CRS3 ( p=0.048) Finally, we found out that a favorable KELIM was significantly associated with CRS3 in the all-comers patients ( p=0.007) and in the BRCAwt ( p=0.04), but it was not predictive of PARPi response. Conclusions: Our findings suggested that the higher the CRS at the interval cytoreduction, the better the subsequent PARPi response. CRS correlates with PARPi response, as the HRD test does in other clinical trials and it may be considered as a surrogate of HRD status. We have planned to retrospectively perform HR test on a total sample size of 77 patients who received PARPi to corroborate this hypothesis. [Table: see text]
Effect of hypoxic status on survival and therapeutic responses in gastric cancer.
Authors: Chan Dai, Xiaohong Duan, Chunyan Yang, Qiming Zhou, Zhihua Pei, Dongliang Wang, Yueyu Fang
Journal: Journal of Clinical Oncology (2023)

e16003 Background: As a significant factor of tumor microenvironment (TME), hypoxia is closely related to cancer metastasis, immune escape and drug resistance. The potential prognosis of hypoxia, as well as its influence on the TME, and therapeutic response have not yet been comprehensively studied in gastric cancer (GC). Here, we developed a prognosis risk assessment model (hypoxia_pred model) based on genes related to hypoxia, and further explored the exact role an impact of hypoxia in GC. Methods: Clinical information and gene expression profile were obtained from Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). 375 patients from TCGA-STAD cohort were used as training set. A 21-hypoxic genes expression dataset from TCGA-STAD was performed an unsupervised clustering analysis for different molecular subtypes of GC. Genes associated prognosis were screened by univariate Cox analysis with a cutoff of pvalue＜0.05. The prognostic risk model based on 9-genes transcriptome data of both hypoxia and prognosis related genes was constructed by Least Absolute Shrinkage and Selection Operator regression analysis. Another two gene expression datasets including 409 patients from GEO (GSE62254 and GSE26901) were employed for verifying the forecast performance of this model. In addition, we used ESTATE and single sample Gene Set Enrichment Analysis (ssGSEA) to explore tumor immune infiltration and potential molecular mechanism of hypoxia in GC. We also evaluated the influence of hypoxia on the prognosis, targeted therapy and immunotherapy of GC patients by survival analysis, targeted drug sensitivity analysis and the assessments of the Cancer Immunome Atlas database. Results: We found hypoxia_pred model is a valuable predictor for the survival of GC in validation cohort (AUC &gt; 0.7). AUC for 1- and 3-year overall survival of GC patients in the TCGA cohort were 0.71 and 0.73. In GC, it was supposed that the aggravation of hypoxia was accompanied by the increase of immune rejection phenotype and the infiltration of immunosuppressive cells. In the validation set, patients predicted high risk by the model have worse immunotherapeutic response and prognosis, and may profit from drugs that inhibit cell cycle signaling pathways. In addition, the outcomes by hypoxia_pred for changes in TME, efficacy of immunotherapy and drug sensitivity were quite hypoxia_pred. targeted drug sensitivity, immune microenvironment, biological function, immunotherapeutic response, and immune cell infiltration were found to be significantly different in those molecular subtypes and risk groups. Conclusions: The model based on hypoxic environment provides theoretical foundation for predicting tumor prognosis and clinical treatment, and may improve the prognosis of GC patients by recommending personalized immunotherapy.
Tumor immune environment in multiple primary malignancies involving colorectal cancers: Comparison with single primary colorectal cancers.
Authors: Junyi Chen
Journal: Journal of Clinical Oncology (2023)

e15536 Background: Multiple primary malignancies (MPM) are characterized by two or more primary tumors in an individual patient, excluding relapse or subordinate relationship. Because the therapeutic options usually become limited, the diagnosis of MPM cause a lot of troubles to both clinicians and patients. A comprehensive investigation in comparing the tumor immune environment in MPM involving colorectal cancers (CRC) with single primary CRC will provide clues for the etiology and the management of MPM. Methods: Three patients with MPM involving CRC and twenty four patients with single primary CRC from our hospital were enrolled in the study. FFPE samples from colorectal lesions were analyzed for the tumor infiltrating lymphocytes [PD-L1+, PD-1+, CD3+, CD4+, CD8+, CD20+, FoxP3+, CD56+, CD163+, CD68+] by multiplex immunofluorescence technique. The tumor-enriched segments and stroma areas annotated by pathologists on images. Then artificial intelligence (AI) employing algorithms of image processing, machine learning, and deep learning techniques distinguished the core and peritumor areas, and calculated the density (counts per mm2) of each marker in two regions. A nonparametric approach (Kruskal–Wallis) was used to compare the density of immune cells between MPM involving CRC and single primary CRC groups. Results: The density of CD4+, CD56 dim , FoxP3+ cells in patients with single primary CRC were significantly higher than those in MPM both in the stroma and tumor-enriched segments (all, p &lt; 0.05). In the tumor-enriched segments, the density of PD-1+ in patients with single primary CRC was also significantly more than that in MPM. Moreover, the density of PD-1+CD8+ cells in patients with single primary CRC showed a trend of higher density than those in MPM patients in the stroma area (p = 0.06). However, the density of PD-1+ and PD-1+CD8+ cells did not show significant differences related to cancer types (MPM and single primary CRC) in the stroma. Other indicators such as CD3+, CD20+, CD8+, CD68+CD163+, CD68+CD163-, CD56 bright and PD-L1+, had no significant difference related to cancer types (MPM and single primary CRC) regardless of the area (tumor-enriched segments and stroma area). Conclusions: We identified that the tumor infiltrating lymphocytes such as CD4+ cells infiltrated more in single primary CRC than those in MPM involving CRC, suggesting that MPM involving CRC may unresponsive to immunotherapy monotherapy. With preclinical studies suggesting potential for synergistic effects, combining immunotherapies may be a promising approach to treat MPM, which requires a further validation with a larger sample size.
The genomic landscape of adolescent and young adult (AYA) malignancies using DNA and RNA-based next generation sequencing.
Authors: Maryam B. Lustberg, Kristiyana Kaneva, Emily Teslow, Elizabeth Mauer, Noah Federman, Ann-Kathrin Eisfeld
Journal: Journal of Clinical Oncology (2023)

e15091 Background: Survival for adolescents and young adult (AYA) cancer patients (defined as age 15-39 years by the NCI) has not improved compared to survival outcomes in pediatric and older adult patients. Several factors contribute to the outcomes disparity, including lack of access to novel treatments. Currently, only a fraction of AYA cancer patients receive advanced genomic testing. Herein, we aim to characterize the molecular landscape of AYA cancers. Methods: De-identified records of 2,706 AYA patients diagnosed with solid tumors and hematologic malignancies who received Tempus xT next-generation sequencing (NGS) were identified. The prevalence of pathogenic/likely pathogenic (P/LP) single-nucleotide variants (SNVs), insertions/deletions (indels), fusions, and copy number alterations were assessed to describe the somatic landscape. Tumor biomarkers, such as microsatellite instability (MSI) and tumor-mutational burden (TMB) were also analyzed. Results: The cohort consisted of 2,706 AYA patients diagnosed with: central nervous system (N = 779), breast cancer (N = 700), bone and soft tissue sarcomas (N = 226), hematologic (N = 198), and gastrointestinal (GI) (N = 803) malignancies. Among 407 high-grade gliomas (HGG WHO Grade 3 &amp; 4), variants in TP53 167 (41%), 136 (33%) IDH1, 125 (31%) ATRX, and 48 (12%) TERT were seen. Among the 82 patients with low-grade glioma (LGG, WHO Grade 1 &amp; 2), 42 (51%) had a variant in IDH1, 40 (49%) TP53, and 35 (43%) ATRX. Among 269 patients with HR+ HER2- breast cancer, 82 (30%) had variants in TP53, 66 (25%) PIK3CA, 46 (17%) GATA3, 43 (16%) FGFR1 and 34 (13%) in ESR1. In triple-negative breast cancers (TNBC), 95 (77%) had a variant in TP53, and 9 (7.3%) in BRCA1. In ewing sarcomas (N = 36), 28 (78%) patients had a fusion with EWSR1, with TP53, STAG2, FGFR2, and RET altered in 2 (5.6%) patients. Within osteosarcomas (N = 46), 12 (26%) patients had a variant in TP53 and 9 (20%) in RB1 . In the AML subgroup (N = 34), WT1 was altered in 5 (15%) and FLT3 in 4 (12%) cases. Finally, in the GI cohort (806), 22 (5%) cases were MSI-H. Within colorectal cancer patients (N = 446), 247 (55%) patients had a variant in TP53, 150 (34%) in KRAS, 64 (14%) in PIK3CA, and several with NRG1 (8, 1.8%) and NTRK (3, 0.7%) fusions. Conclusions: We describe the somatic landscape of common malignancies in one of the largest AYA datasets. Additional analyses will focus on how this landscape differs from non-AYA age groups.
Prognostic impact of depth of response (DpR) and early tumour shrinkage (ETS) in patients (pts) with <i>BRAF V600E</i> mutated (mut) metastatic colorectal cancer (mCRC) receiving targeted therapy (TT) as second-line treatment.
Authors: Guglielmo Vetere, Marco Maria Germani, Maria Bensi, Carlotta Antoniotti, Sara Lonardi, Alessandro Passardi, Filippo Ghelardi, Maria Alessandra Calegari, Beatrice Borelli, Sara Santucci, Rossana Intini, Eleonora Cristarella, Mara Persano, Alberto Puccini, Daniele Lavacchi, Laura Noto, Clizia Zichi, Riccardo Giampieri, Massimiliano Salati, Chiara Cremolini
Journal: Journal of Clinical Oncology (2023)

3568 Background: Encorafenib and cetuximab (EC) is the standard of care for pre-treated patients (pts) with BRAF V600E mut mCRC. DpR and ETS previously showed a strong correlation with survival outcomes in mCRC pts receiving 1 st -line therapy. We assessed these tumour dynamic response parameters and their association with clinical outcome in pts with BRAF V600E mut mCRC treated with TT in second-line. Methods: Patients treated in a real-life setting with EC or EC plus binimetinib (ECB) in 20 Italian centres were included. Pts with measurable disease and at least one available disease reassessment by CT scan were eligible. Pts experiencing disease progression as best response (i.e. primary resistant) were not evaluable for DpR and ETS. Associations between DpR and ETS and progression free survival (PFS) and overall survival (OS) were tested by univariate and multivariate models. Results: 105 pts were included: 89 (85%) and 16 (15%) pts were treated with EC and ECB, respectively. Median PFS and OS were 5.2 and 10.3 mos, respectively. Twenty-nine pts (28%) were primary resistant, while 76 (72%) pts achieved disease control (51 [48%] and 25 [24%] pts had SD or CR/PR, respectively). Among baseline characteristics, the presence of peritoneal metastases was a predictor of primary resistance (p = 0.04). Among pts evaluable for response parameters (n = 76), median DpR was 15% and ETS occurred in 28 pts (37%). Mucinous histology was associated with a significantly lower magnitude of DpR (p = 0.005) and a lower rate of ETS (p = 0.002). A significant association between DpR and PFS was observed, both as a dichotomous ( ie, ≥ or &lt; median value) and continuous variable in univariate and multivariate analyses. Also RECIST response correlated with PFS in the two models (table). DpR was associated with OS in the univariate analyses, but this was not confirmed in the multivariate models (table). No correlation between ETS and survival, either as a dichotomous ( ie, ≥ or &lt; 20%) or a continuous variable, was observed. Conclusions: Having a DpR of at least 15% predicts longer PFS and OS in patients with BRAF V600E mut mCRC receiving TT as second-line treatment. An independent cohort of pts treated with second-line chemotherapy +/- antiangiogenic is under investigation as control group. [Table: see text]
Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA).
Authors: Van K. Morris, Greg Yothers, Scott Kopetz, Shannon L Puhalla, Peter C. Lucas, Atif Iqbal, Patrick M Boland, Dustin A. Deming, Aaron James Scott, Howard John Lim, Theodore S. Hong, Norman Wolmark, Thomas J. George
Journal: Journal of Clinical Oncology (2023)

TPS3625 Background: Detection of circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells after surgical resection. For patients (pts) with colon cancer (CC), the detection of ctDNA is associated with persistent disease after resection and outperforms traditional clinical and pathological features in prognosticating risk for recurrence. However, for pts with stage II CC, there are currently no validated biomarkers predicting benefit in identifying pts whose residual disease cancer be cleared by adjuvant chemotherapy. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N = 1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for active surveillance (i.e., not needing adjuvant chemotherapy) will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the Guardant Reveal assay, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. Enrollment continues across North America to the 1408-patient phase III endpoint. NCT#: 04068103. Support: U10CA180868, -180822; UG1CA189867; GuardantHealth. Clinical trial information: NCT04068103 .
Personalized circulating tumor DNA (ctDNA) analysis in predicting residual disease after neoadjuvant chemoradiotherapy (nCRT) for esophageal squamous cell carcinoma (ESCC).
Authors: Zhichao Liu, Yang Yang, Jun Liu, Hong Zhang, Hong Yu, Yuchen Han, Xiao-Long Fu, Hao Zhang, Jianxing Xiang, Songan Chen, Xi Li, Mingjun Zhu, Zhigang Li
Journal: Journal of Clinical Oncology (2023)

e16062 Background: For ESCC patients who receive nCRT, high pathological complete response (pCR) rates could be achieved. A “Watch and Wait” strategy has been proposed for patients with clinical complete response (cCR) after nCRT. However, clinical assessments would inevitably misclassify non-pCR as cCR. We previously showed that ctDNA analysis with tumor-naïve fixed panel could improve the prediction of cCR. This study further investigates the value of personalized ctDNA analysis in predicting tumor response and residual disease after nCRT in ESCC. Methods: This is a side study of the prospective, diagnostic preSINO trial (NCT03937362). After completion of nCRT, patients underwent one or two clinical response evaluations (CREs) before planned surgery. CRE‐1 was 4–6 weeks after nCRT. CRE‐2 was 10–12 weeks after nCRT for patients without histological evidence of residual tumor at CRE-1. Individual tumors and matched white blood cells at baseline (B0) were whole-exome sequenced and somatic mutations were identified. Serial plasma samples were analyzed by brPROPHET tracking up to 50 somatic mutations at three timepoints: B0, CRE-1, CRE-2. This assay was developed to detect residual disease with a limit of detection of 0.004% and sample-level specificity of greater than 99% in the analytical validation. Residual disease was also detected and quantified through TNFP in the same samples for a head-to-head comparison. We correlated post-nCRT ctDNA status with pCR and major locoregional residual disease (MLRD) (&gt;10% residual cancer or any residual nodal disease). Results: At this interim analysis, 55 ESCC patients (stage III, 87%) who received per-protocol treatments had sufficient sample to test ctDNA. The pCR rate was 27 % (15/55). 98% (2918/2966) of variants selected for patient-specific panel design were private to a specific patient, only 3% (92/2966) of variants were included in the fixed panel. After nCRT, ctDNA was detected by brPROPHET prior to nCRT in 100% of samples (n=55), significantly higher than that by TNFP assay (73%, 40/55). ctDNA was detected in 55% (30/55) of patients at CRE-1, 43% (10/23) at CRE-2. Importantly, the brPROPHET achieved higher sensitivity than TNFP in predicting non-pCR and MLRD owing to its ability to detect extremely low ctDNA fractions (to 1.14 x 10 -5 ). Moreover, combining brPROPHET with CREs could further improve the sensitivity. Conclusions: Personalized ctDNA analysis can supplement the clinical assessment to decrease the false negative rate in identifying patients with residual disease after nCRT, and might become useful in the “Watch and Wait” strategy for the management of ESCC. Clinical trial information: NCT03937362 . [Table: see text]
Risk factors, clinical characteristics, and treatment outcomes for hepatocellular carcinoma in Rwanda.
Authors: Ange Uwimana, Prince Alain Kubwayo, Damas Dukundane, Menelas Nkeshimana, Ammara Naveed, Neil Gupta, Eric Seruyange, Maarten C Bosland, Fidel Rubagumya
Journal: Journal of Clinical Oncology (2023)

e16339 Background: Hepatocellular carcinoma (HCC) is increasing worldwide with limited treatment options, a poor prognosis, and survival rates of less than 5 years. In Sub-Saharan Africa, over 46,000 new cases are reported every year, and HCC is commonly associated with alcohol consumption, viral hepatitis, especially Hepatitis B (HBV) and C (HCV), aflatoxin exposure, obesity, type II diabetes, and HIV infection. In Rwanda, often young people are diagnosed with HCC in the late stages of the disease, and treatment options are limited. Rwanda has made great achievements in the prevention and treatment of HBV and HCV. However, there is a lack of data on HCC in Rwanda and its associated risk factors. In this study, we report the prevalence of common risk factors, available treatment options, and treatment outcomes among patients with HCC in Rwanda. Methods: This was a retrospective study of patients aged 18 years of age and above diagnosed with HCC from 2016 to 2021 in three tertiary hospitals: University Teaching Hospital of Kigali, King Faisal Hospital, and Rwanda Military Hospitals. Data were abstracted from patients’ paper charts and electronic medical records and recorded in REDCap and analyzed in STATA. Results: Overall, 219 individuals were included in the study. 32.9% were female, the median age was 32 (26–54) years, and 48.4% came from the capital city of Kigali. Only 13.3% of patients had histo-pathological confirmation of HCC, while 86.7 % were diagnosed clinically with radiological images, alpha-fetoprotein, and other clinical findings. The most common risk factors were HCV and HBV infection with a prevalence of 27.4% and 20.1%, respectively. HIV infection and diabetes mellitus were present in 6.9% and 6.2% of patients, respectively. More than 80% of patients had had clinical or ultrasound evidence of cirrhosis, including ascites or hepatic encephalopathy and only 8.9% of patients received Sorafenib, and no patient had surgical resection, ablation, or liver transplant. Only 15.1% of patients received palliative care with opiate therapy. Among all patient diagnosed with HCC, 36% died within 3 months of diagnosis. Conclusions: In this retrospective study of the three largest treatment centers in Rwanda, the majority of HCC cases occurred at a young age with a high rate of mortality. HBV and HCV were the most frequent risk factors, and the majority of patients had clinical characteristics of decompensated liver failure. There is a clear lack of diagnostic tools, most glaringly pathologic diagnosis, and an extreme lack of treatment options. Increased awareness for HBV and HCV prevention and screening as well as further studies on etiology of HCC cases and management are needed.